A Pilot Study to Measure Upper Extremity H-reflexes Following Neuromuscular Electrical Stimulation Therapy after Stroke

Upper extremity (UE) hemiparesis persists after stroke, limiting hand function. Neuromuscular electrical stimulation (NMES) is an effective intervention to improve UE recovery, although the underlying mechanisms are not fully understood. Our objective was to establish a reliable protocol to measure UE agonist–antagonist forearm monosynaptic reflexes in a pilot study to determine if NMES improves wrist function after stroke. We established the between-day reliability of the H-reflex in the extensor carpi radialis longus (ECRL) and flexor carpi radialis (FCR) musculature for individuals with prior stroke (n = 18). The same-day generation of ECRL/FCR H-reflex recruitment curves was well tolerated, regardless of age or UE spasticity. The between-day reliability of the ECRL H-reflex was enhanced above FCR, similar to healthy subjects [20], with the Hmax the most reliable parameter quantified in both muscles. H-reflex and functional measures following NMES show the potential for NMES-induced increases in ECRL Hmax, but confirmation requires a larger clinical study. Our initial results support the safe, easy, and efficacious use of in-home NMES, and establish a potential method to measure UE monosynaptic reflexes after stroke

A Bayesian comparative effectiveness trial in action: developing a platform for multisite study adaptive randomization

A grant from the One-University Open Access Fund at the University of Kansas was used to defray the author's publication fees in this Open Access journal. The Open Access Fund, administered by librarians from the KU, KU Law, and KUMC libraries, is made possible by contributions from the offices of KU Provost, KU Vice Chancellor for Research & Graduate Studies, and KUMC Vice Chancellor for Research. For more information about the Open Access Fund, please see http://library.kumc.edu/authors-fund.xml.Background In the last few decades, the number of trials using Bayesian methods has grown rapidly. Publications prior to 1990 included only three clinical trials that used Bayesian methods, but that number quickly jumped to 19 in the 1990s and to 99 from 2000 to 2012. While this literature provides many examples of Bayesian Adaptive Designs (BAD), none of the papers that are available walks the reader through the detailed process of conducting a BAD. This paper fills that gap by describing the BAD process used for one comparative effectiveness trial (Patient Assisted Intervention for Neuropathy: Comparison of Treatment in Real Life Situations) that can be generalized for use by others. A BAD was chosen with efficiency in mind. Response-adaptive randomization allows the potential for substantially smaller sample sizes, and can provide faster conclusions about which treatment or treatments are most effective. An Internet-based electronic data capture tool, which features a randomization module, facilitated data capture across study sites and an in-house computation software program was developed to implement the response-adaptive randomization. Results A process for adapting randomization with minimal interruption to study sites was developed. A new randomization table can be generated quickly and can be seamlessly integrated in the data capture tool with minimal interruption to study sites. Conclusion This manuscript is the first to detail the technical process used to evaluate a multisite comparative effectiveness trial using adaptive randomization. An important opportunity for the application of Bayesian trials is in comparative effectiveness trials. The specific case study presented in this paper can be used as a model for conducting future clinical trials using a combination of statistical software and a web-based application. Trial registration ClinicalTrials.gov Identifier: NCT02260388, registered on 6 October 201

The duality of computation

http://www.acm.orgInternational audienceWe present the lambda-bar-mu-mu-tilde-calculus, a syntax for lambda-calculus + control operators exhibiting symmetries such as program/context and call-by-name/call-by-value. This calculus is derived from implicational Gentzen's sequent calculus LK, a key classical logical system in proof theory. Under the Curry-Howard correspondence between proofs and programs, we can see LK, or more precisely a formulation called LK-mu-mu-tilde, as a syntax-directed system of simple types for lambda-bar-mu-mu-tilde-calculus. For lambda-bar-mu-mu-tilde-calculus, choosing a call-by-name or call-by-value discipline for reduction amounts to choosing one of the two possible symmetric orientations of a critical pair. Our analysis leads us to revisit the question of what is a natural syntax for call-by-value functional computation. We define a translation of lambda-mu-calculus into lambda-bar-mu-mu-tilde-calculus and two dual translations back to lambda-calculus, and we recover known CPS translations by composing these translations

Database Evaluation for Muscle and Nerve Diseases - DEMAND: An academic neuromuscular coding system

Background: A database which documents the diagnosis of neuromuscular patients is useful for determining the types of patients referred to academic centers and for identifying participants for clinical trials and other studies. The ICD-9 or ICD-10 numeric systems are insufficiently detailed for this purpose. Objective: To develop a database for neuromuscular diagnoses Methods: We developed a detailed diagnostic coding system for neuromuscular diseases called DEMAND: Database Evaluation for Muscle and Nerve Diseases that has been adopted by neuromuscular clinics at University of Texas Health Science Center San Antonio (UTHSCSA), Ohio State University (OSU), University of Kansas Medical Center (KUMC), and University of Texas Southwestern (UTSW). At the initial visit, patients are assigned a diagnostic code which can be revised later if appropriate. Fields include patient’s name, date of birth, and diagnostic code. The neuromuscular database consisted of 457 codes. Each code has a prefix (MUS or PNS) followed by a three-digit number. Depending on whether muscle or nerve is primarily involved, there are eight broad groups: motor neuron disease (MUS codes 100-139); neuromuscular junction disorders (MUS 200-217); acquired and hereditary myopathies (MUS 300-600s); acquired and hereditary polyneuropathies (PNS 100-400); mononeuropathies (PNS 500s); plexopathies (PNS 600s); radiculopathies (PNS 700s); and mononeuritis multiplex (PNS 800s). Results: During a period of 10 years, 17,163 of patients were entered (1,752 at UTHSCSA, 1,840 at OSU, 3,699 at KUMC, 9,872 at UTSW). The number of patients in several broad categories are: 3,080 motor neuron disease; 1,575 neuromuscular junction disease; 1,851 muscular dystrophies; 633 inflammatory myopathies; 1,090 hereditary neuropathies; 1,001 immune-mediated polyneuropathies; 620 metabolic/toxic polyneuropathies; 535 mononeuropathies; 296 plexopathies; and 769 radiculopathies. Conclusion: A detailed diagnostic neuromuscular database can be utilized at multiple academic centers. The database should be simple without too many fields to complete, to ensure compliance during busy clinic operations. This database has been very useful in identifying groups of patients for retrospective, observational studies and for prospective treatment studies including trials for Amyotrophic Lateral Sclerosis (ALS), Muscular Dystrophies (MD), Myasthenia Gravis (MG), and retrospective studies of Primary Lateral Sclerosis (PLS), chronic inflammatory demyelinating neuropathy (CIDP), etc

A calibration method for broad-bandwidth cavity enhanced absorption spectroscopy performed with supercontinuum radiation

An efficient calibration method has been developed for broad-bandwidth cavity enhanced absorption spectroscopy. The calibration is performed using phase shift cavity ring-down spectroscopy, which is conveniently implemented through use of an acousto-optic tunable filter (AOTF). The AOTF permits a narrowband portion of the SC spectrum to be scanned over the full high-reflectivity bandwidth of the cavity mirrors. After calibration the AOTF is switched off and broad-bandwidth CEAS can be performed with the same light source without any loss of alignment to the set-up. We demonstrate the merits of the method by probing transitions of oxygen molecules O-2 and collisional pairs of oxygen molecules (O-2)(2) in the visible spectral range

Targeting Protein Homeostasis in Sporadic Inclusion Body Myositis

Sporadic inclusion body myositis (sIBM) is the commonest severe myopathy in patients over age 50. Previous therapeutic trials have targeted the inflammatory features of sIBM, but all have failed. Since protein dyshomeostasis may also play a role in sIBM, we tested the effects of targeting this feature of the disease. Using rat myoblast cultures, we found that up-regulation of the heat shock response with Arimoclomol reduced key pathological markers of sIBM in vitro. Furthermore, in mutant valosin-containing protein VCP mice, which develop an inclusion body myopathy (IBM), treatment with Arimoclomol ameliorated disease pathology and improved muscle function. We therefore evaluated the safety and tolerability of Arimoclomol in an investigator-lead, randomised, double-blind, placebo-controlled, proof-of-concept patient trial and gathered exploratory efficacy data which showed that Arimoclomol was safe and well tolerated. Although Arimoclomol improved some IBM-like pathology in vitro and in vivo in the mutant VCP mouse, we did not see statistically significant evidence of efficacy in this proof of concept patient trial

Towards a canonical classical natural deduction system

This paper studies a new classical natural deduction system, presented as a typed calculus named \lml. It is designed to be isomorphic to Curien-Herbelin's calculus, both at the level of proofs and reduction, and the isomorphism is based on the correct correspondence between cut (resp. left-introduction) in sequent calculus, and substitution (resp. elimination) in natural deduction. It is a combination of Parigot's $\lambda\mu$-calculus with the idea of ``coercion calculus'' due to Cervesato-Pfenning, accommodating let-expressions in a surprising way: they expand Parigot's syntactic class of named terms. This calculus aims to be the simultaneous answer to three problems. The first problem is the lack of a canonical natural deduction system for classical logic. \lml is not yet another classical calculus, but rather a canonical reflection in natural deduction of the impeccable treatment of classical logic by sequent calculus. The second problem is the lack of a formalization of the usual semantics of Curien-Herbelin's calculus, that explains co-terms and cuts as, respectively, contexts and hole-filling instructions. The mentioned isomorphism is the required formalization, based on the precise notions of context and hole-expression offered by \lml. The third problem is the lack of a robust process of ``read-back'' into natural deduction syntax of calculi in the sequent calculus format, that affects mainly the recent proof-theoretic efforts of derivation of $\lambda$-calculi for call-by-value. An isomorphic counterpart to the $Q$-subsystem of Curien-Herbelin's-calculus is derived, obtaining a new $\lambda$-calculus for call-by-value, combining control and let-expressions.Fundação para a Ciência e a Tecnologia (FCT

Interleukin-21 Is Required for the Development of Type 1 Diabetes in NOD Mice

OBJECTIVE: Interleukin (IL)-21 is a type 1 cytokine that has been implicated in the pathogenesis of type 1 diabetes via the unique biology of the nonobese diabetic (NOD) mouse strain. The aim of this study was to investigate a causal role for IL-21 in type 1 diabetes. RESEARCH DESIGN AND METHODS: We generated IL-21R–deficient NOD mice and C57Bl/6 mice expressing IL-21 in pancreatic β-cells, allowing the determination of the role of insufficient and excessive IL-21 signaling in type 1 diabetes. RESULTS: Deficiency in IL-21R expression renders NOD mice resistant to insulitis, production of insulin autoantibodies, and onset of type 1 diabetes. The lymphoid compartment in IL-21R−/− NOD is normal and does not contain an increased regulatory T-cell fraction or diminished effector cytokine responses. However, we observed a clear defect in autoreactive effector T-cells in IL-21R−/− NOD by transfer experiments. Conversely, overexpression of IL-21 in pancreatic β-cells induced inflammatory cytokine and chemokines, including IL-17A, IL17F, IFN-γ, monocyte chemoattractant protein (MCP)-1, MCP-2, and interferon-inducible protein-10 in the pancreas. The ensuing leukocytic infiltration in the islets resulted in destruction of β-cells and spontaneous type 1 diabetes in the normally diabetes-resistant C57Bl/6 and NOD × C57Bl/6 backgrounds. CONCLUSIONS: This work provides demonstration of the essential prodiabetogenic activities of IL-21 on diverse genetic backgrounds (NOD and C57BL/6) and indicates that IL-21 blockade could be a promising strategy for interventions in human type 1 diabetes